rs139912214

Positions:

• chr1-47281003-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001048166.1(STIL):​c.1455G>C​(p.Leu485Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00207 in 1,614,076 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: STIL NM_001048166.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:10
• Conservation: PhyloP100: 0.337

Genes affected

STIL (HGNC:10879): (STIL centriolar assembly protein) This gene encodes a cytoplasmic protein implicated in regulation of the mitotic spindle checkpoint, a regulatory pathway that monitors chromosome segregation during cell division to ensure the proper distribution of chromosomes to daughter cells. The protein is phosphorylated in mitosis and in response to activation of the spindle checkpoint, and disappears when cells transition to G1 phase. It interacts with a mitotic regulator, and its expression is required to efficiently activate the spindle checkpoint. It is proposed to regulate Cdc2 kinase activity during spindle checkpoint arrest. Chromosomal deletions that fuse this gene and the adjacent locus commonly occur in T cell leukemias, and are thought to arise through illegitimate V-(D)-J recombination events. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0040679574).
• BP6: Variant 1-47281003-C-G is Benign according to our data. Variant chr1-47281003-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 160052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-47281003-C-G is described in Lovd as [Pathogenic]. Variant chr1-47281003-C-G is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
STIL	NM_001048166.1	c.1455G>C	p.Leu485Phe	missense_variant	12/17	ENST00000371877.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
STIL	ENST00000371877.8	c.1455G>C	p.Leu485Phe	missense_variant	12/17	1	NM_001048166.1	P5

Frequencies

GnomAD3 genomes AF: 0.00193 AC: 293 AN: 152130 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00393

Gnomad ASJ AF: 0.00778

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00276

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00219 AC: 551 AN: 251306 Hom.: 4 AF XY: 0.00215 AC XY: 292 AN XY: 135816

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00214

Gnomad ASJ exome AF: 0.00884

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00209 AC: 3056 AN: 1461828 Hom.: 5 Cov.: 32 AF XY: 0.00210 AC XY: 1525 AN XY: 727206

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00215

Gnomad4 ASJ exome AF: 0.00918

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000696

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00245

GnomAD4 genome AF: 0.00192 AC: 293 AN: 152248 Hom.: 1 Cov.: 32 AF XY: 0.00201 AC XY: 150 AN XY: 74444

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00778

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00276

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00285 Hom.: 3

Bravo AF: 0.00208

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00337 AC: 29

ExAC AF: 0.00213 AC: 259

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00425

EpiControl AF: 0.00415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 02, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 26, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 21, 2024	The p.Leu438Phe variant in STIL is classified as likely benign because it has been identified in 0.9% (267/29604) of Ashkenazi Jewish chromosomes, 0.4% (29/6060) of Middle Eastern chromosomes and 0.3% (156/60012) of Admixed American chromosomes, including 6 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0). In addition, computational prediction tools predict that this variant does not impact the protein. ACMG/AMP Criteria applied: BS1, BP4. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 19, 2015	- -

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	STIL: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 08, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 17, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	- -

Abnormal brain morphology Pathogenic:1

Likely pathogenic, flagged submission

research

Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine

-

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 20, 2013

This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Microcephaly 7, primary, autosomal recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.21	T;.;.;.;T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.73	T;T;T;T;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.0041	T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L;.;L;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.6	N;.;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.091	T;.;T;T;T
Sift4G	Benign	0.29	T;T;T;T;.
Polyphen		0.058	B;.;B;B;B
Vest4		0.030
MutPred		0.092		Loss of glycosylation at S484 (P = 0.1331);.;Loss of glycosylation at S484 (P = 0.1331);Loss of glycosylation at S484 (P = 0.1331);.;
MVP		0.32
MPC		0.13
ClinPred		0.00071	T
GERP RS		-0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.042
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs139912214; hg19: chr1-47746675;